Solid-organ transplantation in older adults: current status and future research.

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

Cardiovascular fitness and exercise as determinants of insulin resistance in postpubertal adolescent females.

In obese adolescents, body mass index (BMI) is a poor predictor of insulin resistance, and the potential role of diminished physical activity has not been quantitated. We measured possible determinants of sensitivity to insulin in 53 adolescent females with a BMI between the 10th and the 95th percentile. We hypothesized that across weight and fitness spectra, relative fat mass, rather than BMI, and cardiovascular fitness would be predictors of insulin resistance. We measured body composition by total-body dual x-ray absorptiometry. Self-reported weekly frequency of aerobic exercise for 1 h (RDE) was recorded, and maximal oxygen consumption (VO(2)max) was measured. Insulin sensitivity was estimated by homeostasis model assessment index (HOMA(IR)) derived from fasting glucose and insulin concentrations. BMI was not related to HOMA(IR) (P = 0.20), RDE showed a marginal relationship (P = 0.049), whereas percent body fat and VO(2)max were significantly related to HOMA(IR) (P = 0.01 and 0.0008, respectively). In a multiple regression model, VO(2)max was a more critical determinant of insulin resistance than percent body fat (P = 0.03 vs. P = 0.67) or RDE (P = 0.01 vs. 0.51). For prevention strategies in youth, physical inactivity may represent a greater metabolic risk than obesity alone.

Effect of aging and obesity on insulin responsiveness and glut-4 glucose transporter content in skeletal muscle of Fischer 344 x Brown Norway rats.

This study investigated the metabolic changes with age in the Fischer 344 x Brown Norway rat and its suitability as an animal model of postmaturational insulin resistance. Specifically, we determined whether an age-associated decrease in glucose disposal is associated with diminished whole body insulin responsiveness and/or a decrease in glucose transporter (GLUT-4) protein and mRNA content in medial gastrocnemius muscle of male Fischer 344 x Brown Norway rats of ages 8, 18, and 28 months. Fasting plasma glucose was unchanged with age. There was a significant age effect on visceral adiposity, fasting plasma insulin levels, insulin responsiveness, and GLUT-4 protein content. Insulin responsiveness and GLUT-4 protein were lower in the 18-month-old rats than in the 8-month-old rats. The findings of age-associated increases in visceral adiposity and insulin resistance, and decreases in GLUT-4 in the Fisher 344 x Brown Norway rat, suggest that this rat strain may be an appropriate model for studying the effects of aging on glucose homeostasis.

Norepinephrine infusion during moderate-intensity exercise increases glucose production and uptake.

A role for the increase in circulating norepinephrine (NE) during intense exercise [IE; > or = 80% maximum O(2) uptake (VO(2max))] in the marked increment in glucose rate of production (Ra) during IE is hypothesized. Seven fit male subjects (27 +/- 2 yr old; body mass index, 23 +/- 1 kg/m(2); VO(2max), 63 +/- 5 mL/kg.min) underwent 40 min of postabsorptive moderate-intensity (53% VO(2max)) cycle ergometer exercise (126 +/- 14 W), once without [control (CON)] and once with NE infusion (0.1 microg/kg.min) from 30-40 min (NE). With infusion, plasma NE reached 15.9 +/- 1.0 nM (8-fold rest, 2-fold CON). Ra doubled to 4.40 +/- 0.44 in CON, but rose to 7.55 +/- 0.68 mg/kg.min with NE infusion (P = 0.003). Ra correlated strongly (r(2) = 0.92, P < 0.02) with plasma NE during and immediately after infusion. With NE infusion, peak glucose uptake [rate of disappearance (Rd), 6.57 +/- 0.59 vs. 4.53 +/- 0.55 mg/kg.min, P < 0.02] and glucose metabolic clearance rate (P < 0.05) were higher than in CON. Glycemia rose minimally during the NE infusion but did not differ between groups at any time during exercise. Glucagon-to-insulin ratio increased minimally, and epinephrine increased approximately 2.5- to 3-fold at peak but did not differ between groups. Thus, NE infusion during moderate exercise led to increments in Ra and Rd in fit individuals, supporting a possible contributory role for the increase of plasma NE in IE. NE effects on Rd and metabolic clearance rate during exercise may differ from its effects at rest.

Caloric restriction mimetics: metabolic interventions.

Caloric restriction (CR) retards diseases and aging in laboratory rodents and is now being tested in nonhuman primates. One way to apply these findings to human health is to identify and test agents that may mimic critical actions of CR. Panel 2 focused on two outcomes of CR, reduction of oxidative stress and improved glucoregulation, for which candidate metabolic mimics exist. It was recommended that studies on oxidative stress should emphasize mitochondrial function and to test the efficacy of nitrone and other antioxidants in mimicking CR's effects. Studies should also focus on the long-term effects of compounds known to lower circulating glucose and insulin concentrations or to increase insulin sensitivity. Also, four other developing areas were identified: intermediary metabolism, response to infection, stress responses, and source of dietary fat. These areas are important because either they hold promise for the discovery of new mimetics or they need to be explored prior to initiation of CR trials in humans. Other recommendations were that transgenic approaches and adult-onset CR should be emphasized in future studies.

Synergist muscle ablation and recovery from nerve-repair grafting: contractile and metabolic function.

After nerve-repair grafting of medial gastrocnemius muscle, there is incomplete recovery of specific force and sustainable power, perhaps due to overcompensation by synergistic muscles. We hypothesized that increased workload due to synergist ablation would enhance graft recovery. Contractile and metabolic properties of control and nerve-repair grafted muscles, with and without synergist ablation, were determined after 120 days recovery. Specific force (N/cm(2)) and normalized power (W/kg) were less in the experimental groups compared with controls. Sustained power (W/kg) in the synergist-ablated nerve-repair grafted muscle was higher than nerve-repair grafted muscle, returning to control values. GLUT-4 protein was higher and glycogen content was diminished in both synergist-ablated groups. In summary, synergist ablation did not enhance the recovery of specific force or normalized power, but sustained power did recover, suggesting that metabolic and not mechanical parameters were responsible for this recovery. The enhanced endurance after synergist ablation was accompanied by increased GLUT-4 protein, suggesting a role for increased uptake of circulating glucose during contraction.

Relation of weight gain and weight loss on subsequent diabetes risk in overweight adults.

STUDY OBJECTIVE: To determine whether long term weight gain and weight loss are associated with subsequent risk of type 2 diabetes in overweight, non-diabetic adults. DESIGN: Prospective cohort. Baseline overweight was defined as BMI>/=27.3 for women and BMI>/=27. 8 for men. Annual weight change (kg/year) over 10 years was calculated using measured weight at subjects' baseline and first follow up examinations. In the 10 years after measurement of weight change, incident cases of diabetes were ascertained by self report, hospital discharge records, and death certificates. SETTING: Community. PARTICIPANTS: 1929 overweight, non-diabetic adults. MAIN RESULTS: Incident diabetes was ascertained in 251 subjects. Age adjusted cumulative incidence increased from 9.6% for BMI<29 to 26. 2% for BMI>/=37. Annual weight change over 10 years was higher in subjects who become diabetic compared with those who did not for all BMI<35. Relative to overweight people with stable weight, each kg of weight gained annually over 10 years was associated with a 49% increase in risk of developing diabetes in the subsequent 10 years. Each kg of weight lost annually over 10 years was associated with a 33% lower risk of diabetes in the subsequent 10 years. CONCLUSIONS: Weight gain was associated with substantially increased risk of diabetes among overweight adults, and even modest weight loss was associated with significantly reduced diabetes risk. Minor weight reductions may have major beneficial effects on subsequent diabetes risk in overweight adults at high risk of developing diabetes.

Chemical versus dual energy x-ray absorptiometry for detecting age-associated body compositional changes in male rats.

Aging is associated with increases in body mass and fat mass (FM), whereas fat-free mass (FFM) either decreases or remains unchanged. The purpose of this study was to determine whether dual-energy X-ray absorptiometry (DXA) accurately detects age-associated changes in male Fischer 344 x Brown-Norway rats ages 8, 18, and 28 months. Eviscerated animal carcasses were first examined via the Lunar DPX-IQ DXA (small animal software version 1.0; HiRes (0.6 x 1.2 mm) medium mode). Eviscerated carcasses were then weighed, autoclaved, homogenized, and fat isolated from aliquots of homogenate via methanol/chloroform extraction. In both chemical (CHEM) and DXA analysis, carcass mass (CM), FM, and % fat were significantly higher (P < 0.0001) in the 18 and 28 versus 8-month-old rats. CHEM showed greater FFM in the 18 versus 8 months-old rats but not the 28 months-old animals. DXA was unable to detect the age-associated changes in FFM. Regression analysis showed a strong correlation between CHEM and DXA methods for CM (r = 0.98, P < 0.0001) and FM (r = 0.97, P < 0.0001), but less strong for FFM (r = 0.59, P = 0.0002). In conclusion, compared to CHEM, DXA consistently overestimated CM and FM across the age groups by 9% and 77%, respectively, and underestimated FFM by 5%.

Epinephrine infusion during moderate intensity exercise increases glucose production and uptake.

The glucoregulatory response to intense exercise [IE, >80% maximum O(2) uptake (VO(2 max))] comprises a marked increment in glucose production (R(a)) and a lesser increment in glucose uptake (R(d)), resulting in hyperglycemia. The R(a) correlates with plasma catecholamines but not with the glucagon-to-insulin (IRG/IRI) ratio. If epinephrine (Epi) infusion during moderate exercise were able to markedly stimulate R(a), this would support an important role for the catecholamines' response in IE. Seven fit male subjects (26 +/- 2 yr, body mass index 23 +/- 0.5 kg/m(2), VO(2 max) 65 +/- 5 ml x kg(-1) x min(-1)) underwent 40 min of postabsorptive cycle ergometer exercise (145 +/- 14 W) once without [control (CON)] and once with Epi infusion [EPI (0.1 microg x kg(-1) x min(-1))] from 30 to 40 min. Epi levels reached 9.4 +/- 0.8 nM (20x rest, 10x CON). R(a) increased approximately 70% to 3.75 +/- 0.53 in CON but to 8.57 +/- 0.58 mg x kg(-1) x min(-1) in EPI (P < 0.001). Increments in R(a) and Epi correlated (r(2) = 0.923, P

Glucoregulation during and after intense exercise: effects of alpha-adrenergic blockade.

In intense exercise (>80% maximal oxygen consumption [VO2 max]), the 7- to 8-fold increase in glucose production (Ra) is tightly correlated with the greater than 14-fold increase in plasma norepinephrine (NE) and epinephrine (EPI). To distinguish the relative roles of alpha- and beta-adrenergic receptors, the responses of 12 control (C) lean, healthy, fit young male subjects to 87% VO2 max cycle ergometer exercise were compared with those of 7 subjects (at 83% VO2max) receiving intravenous phentolamine (Ph). The Ph group received a 70-microg/kg bolus and then 7 microg/kg/min from -30 minutes, during exercise and for 60 minutes of recovery. The data were analyzed by comparing exercise responses to exhaustion in Ph subjects (11.4 +/- 0.6 min) with those at both 12 minutes and at exhaustion in C subjects (14.6 +/- 0.3 min) and during recovery. There were no significant differences between groups in the plasma glucose response during exercise, but values were higher in C versus Ph subjects during the first 40 minutes of postexercise "recovery." The Ra response during the first 12 minutes of exercise was not different by repeated-measures ANOVA, reaching 10.6 +/- 1.3 mg/kg/min in C and 9.6 +/- 1.5 in Ph subjects at 12 minutes. However, in C subjects, Ra increased significantly to 14.1 +/- 1.2 mg/kg/min by exhaustion, and remained higher versus Ph subjects until 15 minutes of recovery. The Rd during recovery was not different between groups; thus, the higher Ra in C subjects in early recovery was responsible for the greater hyperglycemia observed in C subjects. Ph subjects showed a more rapid, marked increment (P = .002) in both plasma NE (to 64 v38 nmol/L) and EPI at exhaustion, and catecholamine concentrations remained higher in Ph versus C subjects during recovery. Whereas plasma insulin (IRI) declined in the C group, it increased 3-fold (P = .001) in the Ph group during exercise and until 15 minutes of recovery. Ph had no effect on glucagon (IRG). Thus, the glucagon to insulin ratio decreased in Ph subjects from baseline levels during exercise and early recovery, but increased in C subjects. The increase in Ra among Ph subjects despite the decrease in the glucagon to insulin ratio supports our earlier evidence that these hormones are not principal regulators of the Ra in intense exercise. The shorter time to exhaustion and markedly higher catecholamine levels in Ph subjects limited our ability to isolate the effects of alpha-adrenergic receptors on the Ra.alpha-Adrenergic receptors appear to have little influence on the Rd.

Gender differences in glucoregulatory responses to intense exercise.

We compared glucoregulatory responses to intense exercise (14 min at 88% maximum O(2) uptake) between genders (16 men, 12 women). Analysis of covariance of maximum O(2) uptake showed no gender effect, with 82% of variance due to fat-free mass (FFM). Glycemia rose comparably during exercise but was higher in women during recovery (P = 0.02). Glucose production [rate of appearance (R(a)); in mg/min] increased markedly in both; stepwise multiple regression and analysis of covariance of R(a) (peak and incremental area under the curve) showed no effect of gender, body weight, or FFM. Glucose uptake [rate of disappearance (R(d))] increased less than R(a) and slower in women. R(d) area under the curve related to FFM (P = 0.01) but not gender or body weight. Norepinephrine and epinephrine responses (13-18x baseline) were the same and correlated significantly with R(a). Exercise insulin and glucagon changes were slight, but postexercise hyperinsulinemia was greater in women (P = 0.018), along with higher R(d). Therefore, intense exercise glucoregulation is qualitatively similar between genders, with a "feed-forward" regulation of R(a) (consistent with catecholamine mediation). However, women have a lesser R(d) response, related to FFM. This combination leads to greater recovery-period hyperglycemia and hyperinsulinemia.

Heightened norepinephrine-mediated vasoconstriction in type 2 diabetes.

Adrenergic responsiveness (AR) appears to be increased in subjects with diabetes, but measurement of arterial AR in normotensive people with type 2 diabetes mellitus has not been previously reported. We sought to determine whether, compared with control subjects, there is increased arterial AR in type 2 diabetes mellitus and its relationship to the level of systemic sympathetic nervous system activity (SNSa). We studied 15 type 2 diabetic subjects aged 57 +/- 3 years without hypertension or clinical signs of autonomic neuropathy and 13 age-matched control subjects aged 55 +/- 2 years. We assessed vascular alpha-AR by measuring forearm blood flow (FABF) by venous occlusion plethysmography during intrabrachial artery norepinephrine (NE) and phentolamine infusions, as well as arterial plasma NE levels and the extravascular NE release rate (NE2) derived from 3H-NE kinetics, as estimates of systemic SNSa. The vasoconstricting effect of NE during intrabrachial artery NE infusion was greater in type 2 diabetes compared with control subjects (P = .02). The vasodilating effect of phentolamine was greater in type 2 diabetics compared with control subjects (P = .05), suggesting increased endogenous arterial alpha-adrenergic tone. Arterial plasma NE levels (control v type 2, 1.8 +/- 0.10 v 1.84 +/- 0.14 nmol/L, P = .86) and NE2 (control vtype 2, 11.8 +/- 1.54 v 13.3 +/- 0.89 nmol/min/m2, P = .39) were similar in the two groups. In summary, in type 2 diabetes compared with control subjects, (1) the vasoconstriction response to intraarterial NE is greater, (2) plasma NE and NE2 are similar, suggesting similar levels of systemic SNSa, and (3) arterial alpha-adrenergic tone is greater. We conclude that subjects with type 2 diabetes demonstrate inappropriately increased alpha-AR for their level of systemic SNSa.

Glucoregulation during and after intense exercise: effects of beta-adrenergic blockade in subjects with type 1 diabetes mellitus.

In intense exercise (>80% maximum oxygen uptake) a huge, up to 8-fold increase in glucose production (Ra) is tightly correlated to marked increases in plasma norepinephrine (NE) and epinephrine. Both Ra and glucose uptake (Rd) are enhanced, not reduced, during beta-adrenergic blockade in normal subjects. Beta-blockade also caused a greater fall in immunoreactive insulin (IRI) during exercise, which could, in turn, have increased Ra directly or via an increased glucagon/insulin ratio. To control for adrenergic effects on endogenous insulin secretion, we tested type 1 diabetic subjects (DM) made euglycemic by overnight i.v. insulin that was kept constant in rate during and after exercise. Their responses to postabsorptive cycle ergometer exercise at 85-87% maximum oxygen uptake for approximately 14 min were compared to those of similar male control (CP) subjects. Six DM and seven CP subjects received i.v. 150 microg/kg propranolol over 20 min, then 80 microg/kg x min from -30 min, during exercise and for 60 min during recovery. Plasma glucose increased from similar resting values to peaks of 6.8 mmol/L in DM and 6.5 mmol/L in CP, then returned to resting values in CP within 20 min, but in DM, remained higher than in CP from 8-60 min (P = 0.049). Ra rose rapidly until exhaustion, to 13.3 mg/kg x min in CP and 11.6 in DM (P = NS). Ra declined rapidly in recovery, although somewhat more slowly in DM (P = 0.013 from 2-15 min). The Rd increased to 10.6 in CP and 9.2 mg/kg x min in DM (P = NS), then declined similarly in early recovery, but remained higher in CP from 50-100 min (P = 0.05). The rises in plasma glucose during exercise in both groups were thus due to the increments in Rd less than those in Ra. The higher recovery glucose in DM was due to the slower decline in Ra and the lower Rd in later recovery. IRI was higher in DM than in CP before exercise (P = 0.011), and whereas it decreased in CP (P < 0.05), it increased approximately 2-fold in DM, thus being higher throughout exercise (P = 0.003). The glucagon/insulin ratio was unchanged in DM, but increased in CP during exercise (P = 0.002). NE showed a rapid, marked increment during exercise to peak values of 23.7 nmol/L in CP and 25.7 nmol/L in DM (P = NS), and epinephrine showed parallel responses. Both correlated significantly with the Ra responses. In summary, the Ra responses of both DM and CP during exercise were greater than those of control unblocked subjects (previously reported) despite higher IRI (all exogenous) in DM. This suggests an important contribution of direct alpha-adrenergic stimulation to this Ra effect.

Acute effects of adrenergic-mediated ischemia on nerve conduction in subjects with type 2 diabetes.

Several lines of evidence support peripheral nerve ischemia as a contributing factor in the etiology of human diabetic neuropathy. We questioned whether diabetic subjects with relatively normal nerve function in the baseline state would be more likely than healthy control subjects to show either improvement of ulnar nerve function with acute intraarterial infusion of nitroprusside (vasodilation) or be more sensitive than control subjects to worsening of nerve function with acute intraarterial infusion of norepinephrine (vasoconstriction). We measured forearm blood flow (FABF) using venous occlusion plethysmography and assessed ulnar nerve function at baseline and during two intrabrachial artery infusions. Six nondiabetic control subjects (mean age, 56 years) and 11 subjects with type 2 diabetes (mean age, 58 years) in good general health participated. Only three type 2 diabetic subjects had peripheral sensory neuropathy, which was mild. Among control subjects, there was no significant change in sensory distal latency, motor distal latency, motor proximal latency, or sensory or motor conduction velocity during norepinephrine infusion. In contrast, among type 2 diabetic subjects, there was a significant increase in sensory (baseline vnorepinephrine, 2.73+/-0.10 v 2.94+/-0.10 milliseconds [MS], P< or =.01) and motor distal latencies (baseline v norepinephrine, 2.90+/-0.06 v 3.18+/-0.1 ms, P< or =.001) and motor proximal latency (baseline v norepinephrine, 7.15+/-0.18 v 7.60+/-0.23 ms, P<.01) and a decrease in sensory conduction velocity (baseline v norepinephrine, 52.1+/-2.0 v 47.7+/-1.6 m/s, P<.01) during norepinephrine infusion. There were no consistent changes in nerve function during nitroprusside infusion in either group. In summary, we found that subjects with type 2 diabetes, but not control subjects, demonstrate a decrement in nerve function with vasoconstriction during intraarterial infusion of norepinephrine, but no consistent change during nitroprusside-induced vasodilation. These findings suggest there may be enhanced sensitivity of nerve function to ischemia in type 2 diabetic subjects with mild or absent clinical neuropathy.

Differential effects of BMI on diabetes risk among black and white Americans.

OBJECTIVE: To determine whether the associations of BMI and fat distribution with diabetes risk are modified by race. RESEARCH DESIGN AND METHODS: Data from the National Health and Nutrition Examination Survey, Epidemiologic Follow-up Study (1971-1992), were used to investigate potential interactions of BMI and fat distribution with race. Incident diabetes was defined by self-report of physician-diagnosed diabetes, hospital and nursing home discharge records, and death certificates. RESULTS: Among the 1,531 black and 9,852 white subjects who were nondiabetic at baseline, 1,139 (10.0%) developed diabetes during 20 years of follow-up. Although the cumulative risk of diabetes increased with baseline BMI in all four race-sex groups, the sex-specific odds ratios (ORs) for black:white subjects decreased with increasing BMI. In particular, for BMI of 22 kg/m2, the OR of diabetes for black:white individuals was 1.87 and 1.76 (P < 0.01) for men and women, respectively; for BMI of 32 kg/m2, the OR decreased to 0.99 and 1.20 (NS) for men and women, respectively. Skinfold ratio was also associated with increased diabetes risk in all race-sex groups, but did not modify the association between race and diabetes. CONCLUSIONS: These findings suggest that the effect of BMI on diabetes risk is different for black and white Americans, with a larger risk for blacks than whites at low BMI and an equivalent risk for both groups at high BMI. A lower degree of visceral adiposity among blacks at higher BMI or a greater impact of visceral adiposity among blacks at low BMI may help explain the interaction of race and BMI on diabetes risk.

Glucose infusion partially attenuates glucose production and increases uptake during intense exercise.

Glucose infusion can prevent the increase in glucose production (Ra) and increase glucose uptake (Rd) during exercise of moderate intensity. We postulated that 1) because in postabsorptive intense exercise (>80% maximal O2 uptake) the eightfold increase in Ra may be mediated by catecholamines rather than by glucagon and insulin, exogenous glucose infusion would not prevent the Ra increment, and 2) such infusion would cause greater Rd. Fit young men were exercised at >85% maximal O2 uptake for 14 min in the postabsorptive state [controls (Con), n = 12] or at minute 210 of a 285-min glucose infusion. In seven subjects, the infusion was constant (CI; 4 mg . kg-1 . min-1), and in seven subjects it was varied (VI) to mimic the exercise Ra response in Con. Although glucose suppressed Ra to zero (with glycemia approximately 6 mM and insulin approximately 150 pM), an endogenous Ra response to exercise occurred, to peak increments two-thirds those in Con, in both CI and VI. Glucagon was unchanged, and very small increases in the glucagon-to-insulin ratio occurred in all three groups. Catecholamine responses were similar in all three groups, and correlation coefficients of Ra with plasma norepinephrine and epinephrine were significant in all. In all CI and VI, Rd at rest was 2x Con, increased earlier in exercise, and was higher for the 1 h of recovery with glucose infusion. Thus the Ra response was only partly attenuated, and the catecholamines are likely to be the regulators. This suggests that an acute endogenous Ra rise is possible even in the postprandial state. Furthermore, the fact that more circulating glucose is used by muscle during exercise and early recovery suggests that muscle glycogen is spared.

Cardiac electrophysiologic effects of norepinephrine in human beings.

BACKGROUND: The electrophysiologic effects of norepinephrine (NE) in human beings have not been previously described. METHODS: The electrophysiologic effects of NE infused at a rate of 25 ng/kg/min were determined in 21 patients with a mean age of 41 +/- 11 years and without structural heart disease who underwent an electrophysiology procedure. In a subgroup of 10 patients electrophysiologic parameters were measured at baseline, after the infusion of NE, and after administration of beta-blockade while in continuous NE infusion. RESULTS: The baseline NE plasma concentration of 298 +/- 153 pg/ml increased to 708 +/- 419 pg/ml after the infusion of NE. NE significantly increased the mean blood pressure, sinus cycle length, corrected sinus node recovery time, ventriculoatrial block cycle length, and the atrial and ventricular effective refractory periods. In a subset of 10 patients 0.2 mg/kg propranolol administered during continued infusion of NE resulted in a further increase in sinus cycle length, atrial-His interval, and ventricular refractoriness. CONCLUSION: A physiologic elevation in the plasma NE concentration results in a depression of sinus node function and atrioventricular conduction and in prolongation of atrial and ventricular refractoriness. Some of NE's effects are partially offset by beta-adrenergic stimulation.

Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity.

In subjects with type 2 diabetes in whom an impaired response to an endothelial-dependent vasodilator has been characterized, the populations have also been at least moderately obese. Obesity has been characterized as an independent predictor of endothelial dysfunction in nondiabetic subjects. We hypothesized that in normotensive subjects with type 2 diabetes compared with age-matched control subjects, 1) endothelium-dependent vasodilation, as demonstrated by the forearm blood flow (FABF) response to intraarterial acetylcholine, would be decreased; 2) endothelium-independent vasodilation, as demonstrated by the FABF response to intraarterial nitroprusside, would be similar; 3) the degree of insulin resistance, as measured by the insulin sensitivity index (SI), would predict greater impairment in the FABF response to acetylcholine; and 4) these relationships would be independent of obesity. We measured FABF by venous occlusion plethysmography during brachial arterial infusions of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroprusside in 20 control and 17 subjects with type 2 diabetes. We measured SI using the frequently sampled i.v. glucose tolerance test. Among the diabetic relative to the control subjects we identified a decrease in the acetylcholine-mediated percent increase in FABF (P = 0.02). Using the absolute FABF response to acetylcholine and including adjustments for body mass index and other covariates, the overall group difference remained and was noted to be greatest in those subjects who had lower baseline FABFs. In contrast, no significant difference in the nitroprusside-mediated increase in the percent change FABF was identified between groups (P = 0.30). Finally, the degree of insulin resistance, as measured by SI, did not independently predict greater impairment of the FABF response to acetylcholine. This study is the first to identify specific endothelial cell dysfunction that remains significant after adjustment for obesity in a population of normotensive subjects with type 2 diabetes.

Fructose perfusion in rat mesenteric arteries impairs endothelium-dependent vasodilation.

We demonstrated that the fructose-induced hypertensive rat, representative of the principal metabolic abnormalities found in a majority of hypertensive patients, i.e. hypertriglyceridemia, hyperinsulinemia and insulin resistance (Syndrome X), is associated with an impaired response to endothelium-dependent vasodilators and that fructose may directly contribute to this impairment. Twelve male Wistar rats were divided into two groups, one given 10% fructose (n=6); the other no fructose (n=6) for 40 days in the drinking water. Systolic blood pressure was measured via the tail cuff method. Perfusion pressure responses to acetylcholine, were measured in the isolated perfused mesenteric vascular bed. Constrictor or dilator responses were measured as increases or decreases, respectively, of the perfusion pressure at a constant flow (4 ml/min). Fructose-fed rats had significantly higher blood pressure, insulin and triglyceride levels than control animals. In phenylephrine constricted beds, the endothelium-dependent dilatation to acetylcholine (0.001 to 1 micromol) was attenuated in the fructose-fed group compared to control animals. Whether this abnormality results from the syndromes (hyperinsulinemia, hypertension and hypertriglyceridemia) associated with the fructose-fed animal model is unknown. We therefore hypothesized that fructose can impair the endothelium-dependent vasodilator response. This was evaluated by perfusing mesenteric arteries from normal rats with control mannitol (40 mM) or fructose (40 mM). Endothelium-dependent dilation to acetylcholine was impaired in fructose-perfused mesenteric arteries. Indomethacin restored the vasodilator response to acetylcholine, suggesting that a cyclooxygenase derivative mediates the impaired response. Thus, we conclude that fructose can contribute to the impaired endothelium-dependent response in the fructose-induced hypertensive rat model.